2. Academic Validation
  3. Discovery of M3 Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease

Discovery of M3 Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease

  • J Med Chem. 2021 Jul 8;64(13):9100-9119. doi: 10.1021/acs.jmedchem.1c00204.
Elisabetta Armani 1,  Andrea Rizzi 1,  Carmelida Capaldi 1,  Renato De Fanti 1,  Maurizio Delcanale 1,  Gino Villetti 1,  Gessica Marchini 1,  Anna Rita Pisano 1,  Vanessa Pitozzi 1,  Maria Gloria Pittelli 1,  Marcello Trevisani 1,  Michela Salvadori 1,  Valentina Cenacchi 1,  Paola Puccini 1,  Francesco Amadei 1,  Alice Pappani 1,  Maurizio Civelli 1,  Riccardo Patacchini 1,  Charles A G Baker-Glenn 2,  Hervé Van de Poël 2,  Wesley P Blackaby 2,  Kevin Nash 2,  Gabriele Amari 1
Affiliations

Affiliations

  • 1 Nuovo Centro Ricerche, Chiesi Farmaceutici S.p.A., Largo Belloli 11/a, 43122 Parma, Italy.
  • 2 Chesterford Research Park, Charles River Discovery Research Services UK Ltd, Saffron Walden CB10 1XL, United Kingdom.
PMID: 34142835 DOI: 10.1021/acs.jmedchem.1c00204
Abstract

In this paper, we report the discovery of dual M3 antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3 receptor and the intracellular PDE4 Enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo (inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro (inhibition of TNFα release). Among the best compounds, compound 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.

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